Results of therapy for relapse associated with the loss HLA of heterozygosity in children with acute leukemia

Introduction. The prognosis for patients with relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains extremely unfavorable, with long-term overall survival (OS) rates less than 10 %. One of the major acquired mechanisms of immunological resistance is loss heterozygosity of HLA (LoH) genes located on chromosome 6. For patients who have developed HLA LoH relapse, immunotherapy based on independent antigen recognition pathways such as blinatumomab therapy, CAR-T therapy or second allo-HSCT is being considered.

The aim of the study – to analyze the efficacy of immunotherapy options in children with HLA LoH relapse based on donor lymphocyte infusions (DLI), blinatumomab and second allo-HSCT.

Materials and methods. We have analyzed 26 patients with HLA LoH confirmed relapse with bone marrow involvement after allo-HSCT. Acute myeloid leukemia was detected in 6 (23 %) patients, acute lymphoblastic leukemia (ALL) in 20 (77 %) patients (B-ALL in 16 patients, T-ALL in 4 patients). Most patients were observed after allo-HSCT from a haploidentical donor, in 24 (92 %) patients and 2 (7.6 %) patients developed relapse after allo-HSCT from a full matched related donor. Isolated medullary relapse was diagnosed in 20 patients; combined relapse was noted in 6 patients (with CNS involvement in 5 patients, testicular relapse in 1 patient).

Results. In the bispecific T-cell activator immunotherapy group, 5 patients with ALL received blinatumomab. Blinatumomab in combination with DLI was given to 3 patients. A response to therapy by the clinical and hematological remission was observed in all patients. MRD negative status was achieved in 4 patients. Subsequently, 2 patients developed medullary relapse and died of the disease progression; 1 patient died of neurotoxic complications after second allo-HSCT; 2 patients are alive in remission after the second allo-HSCT, with follow-up of 10 and 4 months. Second allo-HSCT was performed in 8 patients, with donor change in 7 patients. In the comparable analysis of the efficacy of HLA LoH relapse therapy, the 2-year OS in the second allo-HSCT group was 71.4 %, compared to 26.3 % in patients who did not undergo second allo-HSCT with donor change (p = 0.06). Comparing the OS results of patients with second allo-HSCT (n = 7), DLI (n = 8) and other therapy (n = 11), the favorable effect was seen by the second allo-HSCT group, where the OS was 71.4 %, 25 % and 27.3 % respectively (p = 0.045).

Conclusion. The presented analysis of the efficacy of different therapeutic options for HLA LoH relapse shows a significant benefit of the second allo-HSCT in this cohort. The investigation of loss of HLA (LoH) heterozygosity in relapse after allo-HSCT in routine practice may differentiate approaches to relapse therapy and decrease the time frame for the second allo-HSCT.

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